Cell mimetic liposomal nanocarriers for tailored delivery of vascular therapeutics
Cell mimetic liposomal nanocarriers for tailored delivery of vascular therapeutics
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DOI：
10.1016/j.chemphyslip.2018.12.009
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发表时间：
2019-01-01
影响因子：
3.4
通讯作者：
Mountain, Deidra J. H.
中科院分区：
文献类型：
--
作者：
Mattern-Schain, Samuel I.;Fisher, Richard K.;Mountain, Deidra J. H.
脂质体给药系统（LDS）在过去的三十年里一直处于药物纳米技术的最前沿。增加LDS与靶细胞和货物递送的关联对于支持整体纳米药物功效至关重要。我们的实验室的目标是开发LDSs的分子治疗，旨在血管病理学。我们之前已经建立了一个脂质体平台，这是一种有效的递送系统，通过使用聚乙二醇（PEG）修饰的脂质体携带八精氨酸（R8）细胞穿透肽（CPP）的血管细胞类型的RNA干扰。进一步定制脂质体膜以模拟血管细胞膜脂质成分可能是用于增加货物递送的有前途的策略。在这里，我们的目的是开发脂质体制剂，可以利用二酰基甘油（DAG）和磷脂酰丝氨酸（PS），天然存在的脂质物质，已知影响血管细胞功能，作为一种简便和有效的手段，以增加纳米药物的疗效，而不影响临床可行性。我们研究了DAG和PS放大我们先前建立的装载有小干扰核糖核酸（siRNA）货物的LDS平台的细胞摄取的能力。细胞荧光显微镜实验结合定量细胞缔合测定和细胞毒性测定进行，以分析DAG/PS对荧光标记的脂质体向血管平滑肌细胞（VSMC）和血管内皮细胞（VEC）的差异递送以及对脂质体介导的毒性的影响。在这些研究中，观察到与靶细胞相关的显著剂量依赖性增加，以及对细胞活力的细胞类型特异性影响。通过标准纳米颗粒表征方法分析DAG/PS修饰的LDS的稳定性和转染效率，并定量siRNA转染功效以测量作为DAG/PS修饰的函数的递送潜力。我们的研究结果表明，这里测试的信号脂质使我们的LDS架构具有更高的治疗潜力，而不影响稳定性，包封效率或生物相容性，从而提出了一种提高纳米药物疗效和特异性的天然策略。
Liposomal delivery systems (LDSs) have been at the forefront of medicinal nanotechnology for over three decades. Increasing LDS association to target cells and cargo delivery is crucial to bolstering overall nanodrug efficacy. Our laboratory aims to develop LDSs for molecular therapeutics aimed at vascular pathology. We have previously established a liposome platform that is an effective delivery system for RNA interference in vascular cell types by using polyethylene glycol (PEG) decorated liposomes bearing an octa-arginine (R8) cell penetrating peptide (CPP). Further tailoring liposome membranes to mimic vascular cell membrane lipid constituents may be a promising strategy for increasing cargo delivery. Here we aimed to develop liposomal formulations that could make use of diacylglycerol (DAG) and phosphatidylserine (PS), naturally occurring lipid species that are known to influence vascular cell function, as a facile and efficient means to increase nanodrug efficacy without compromising clinical viability. We investigated the ability of DAG and PS to amplify the cellular uptake of our previously established LDS platform loaded with small interfering ribonucleic acid (siRNA) cargo. Cellular fluorescence microscopy experiments were performed in conjunction with quantitative cell association assays and cytotoxicity assays to analyze the effect of DAG/PS on the differential delivery of fluorescently-tagged liposomes to vascular smooth muscle cells (VSMCs) and vascular endothelial cells (VECs) and on liposomal-mediated toxicity. In these studies, significant, dose-dependent increases in association to target cells were observed, as well as cell-type specific effects on cell viability. The stability and encapsulation-efficiency of the DAG/PS-modified LDSs were analyzed by standard nanoparticle characterization methods, and siRNA transfection efficacy was quantified to gauge delivery potential as a function of DAG/PS modification. Our results suggest that the signaling lipids tested here imbue our LDS architectures with increased therapeutic potential, without compromising stability, encapsulation efficiency, or biocompatibility, thus presenting a natural strategy to increase nanodrug efficacy and specificity.